Project Summary/Abstract The general objective of the proposed research is to provide insight into how the locus coeruleus (LC) influences cognitive functioning across the adult lifespan. Recent evidence indicates that the LC, a small brainstem nucleus, has a fundamental role in cognitive aging. Critically, it has been proposed that Alzheimer's disease pathology begins in the LC, and it is likely that age-related deficits in the LC affect cognitive abilities even before clinically relevant symptoms begin to emerge. The proposed research integrates cognitive, physiological, neuroimaging, and neuropsychological approaches to investigate the relationship between the structure and function of the LC and a subset of cognitive abilities that are dependent on the LC. A theoretical framework developed in our laboratory posits that the ability to selectively focus under arousal by inhibiting irrelevant or distracting information is dependent on the locus coeruleus-norepinephrine (LC-NE) system. The primary goal of this proposal is to test the hypothesis that age-related deficits in the LC-NE system disrupt arousal's ability to facilitate both selective attention and selective memory. Using a series of experimental tasks, it is hypothesized that older adults will exhibit greater difficulty inhibiting attention and memory of irrelevant information under arousal, relative to younger adults. Levels of sympathetic arousal will be manipulated in these experimental tasks by showing highly negative images, increasing cognitive load, and using a handgrip squeeze task. The proposed research will use pupillometry as an indirect measure of LC-NE activity and specialized neuroimaging techniques to localize and measure the signal intensity of the LC-NE system. It is anticipated that individual differences in the ability to inhibit distracting information during these experimental tasks will correlate with the structural and functional integrity of the LC-NE system. The final goal of this proposal is to test the hypothesis that deterioration of the LC-NE system in older adults is associated with worse performance on standardized neuropsychological tests of executive functioning and memory. Results from the proposed research will deepen and broaden our understanding of how the LC modulates cognitive processing across the adult lifespan. These findings could provide insight into the type of cognitive impairments that emerge at the very earliest stages of Alzheimer's disease and precede the cortical spread of this neurodegenerative disease.